This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The outcome for patients with recurrent/metastatic lung cancer has not changed over the last 2 decades and most patients die of their disease. New anti-lung cancer therapies are needed and immunotherapy holds the promise to fulfill this need. The body's immune defense against cancers often fails because cancers either do not induce or actively inhibit immunity. We will counteract these limitations by i) engineering killer T cells or recognize structures on lung cancer cells and ii) to resist the defenses imposed by the cancer cell environment. Using gene transfer technology, it may be possible to take advantage of the tumor killing ability of killer T cells and render them resistant to inhibitory factors secreted by tumor cells. We propose taking the patients own T cells and putting into them two genes. The first gene is for an artificial structure (receptor) that will direct the T cells to the tumor and the second gene is for a dominant negative receptor (DNR), which renders T cells resistant against one of the major inhibitory factors secreted by lung cancer cells. We will place the two genes into T cells that are pre-selected for their ability to recognize the Epstein Barr virus which is chronically present in most people. Because these EBV-specific T cells meet the virus positive cells as well as tumor cells, they receive extra stimulation. We will put the genes for the artificial receptor and the DNR into patients EBV-specific T cells using a modified virus (Moloney retroviral vector). These modified T-cells will then be given directly into the patient s blood stream through a central line or a vein. Patients will be treated in the clinic and will be monitored closely for several hours after infusion. We will collect samples of blood from peripheral blood at regular intervals. We will look for the safety, the persistence and the function of the cells we put into the patients. Ultimately we hope to get evidence that these modified T cells are effective at fighting the cancer.